August 2016, Vol. 5, No. 6
AML Vaccine Induces Immunologic Responses in Phase 2 Study
Serial vaccination with galinpepimut-S (GPS) induces immunologic responses in patients with acute myeloid leukemia (AML) who are in remission. Both disease-free survival (DFS) and overall survival (OS) appear to be improved in AML patients with an immune response to GPS, according to data from a phase 2 trial of GPS.
AML has long been recognized as an immunoresponsive disease in the transplant setting. “Many investigators have attempted to recapitulate this well-described immunologic effect outside the transplant setting using a variety of approaches,” said lead investigator Peter George Maslak, MD, Chief of the Immunology Laboratory Service, Memorial Sloan Kettering Cancer Center, New York City. “To that end, our group…has focused on a vaccine-based approach targeting the WT1 antigen.”
He explained why WT1 is a relevant immunologic target. The WT1 gene is a transcription factor with limited expression in normal tissue. It is overexpressed in myeloid malignancies, including AML. WT1 is found in early leukemia progenitors and possibly leukemic stem cells. Also, the expression of WT1 has been reported to be a prognostic marker and an indicator of minimal residual disease in AML and myelodysplastic syndrome. It is processed and presented to the immune system as evidence of the ability to detect WT1-specific cytotoxic T lymphocytes (CTLs) in patients with AML and chronic lymphocytic leukemia who are in remission.
Heteroclitic analog WT1 peptides can induce a reactive T-cell response to native peptides, and peptide vaccines derived from WT1 can induce CTL recognition and killing of WT1-expressing leukemia cell lines.
The vaccine consists of 2 native and 2 heteroclitic WT1 peptides designed to activate CD4+ and/or CD8+ T cells. In a pilot study reported previously, GPS was found to be safe and immunogenic, with prolonged survival following vaccination of AML patients.
The study included 22 AML patients who completed chemotherapy and were in remission by standard response criteria. Patients received 6 vaccinations administered with adjuvant Montanide/granulocyte-macrophage colony-stimulating factor over 10 weeks, with the potential to receive 6 additional monthly doses if there was progression of disease after assessment at 12 weeks.
Prognostic risk was favorable in 8 patients, intermediate-1 in 7 patients, intermediate-2 in 3, adverse in 3, and undetermined in 1. Ninety-five percent of patients received a standard cytarabine/anthracycline induction regimen.
Sixty-four percent of patients received 6 vaccinations, and 45% completed all 12 vaccine doses. Fifteen patients relapsed (10 while receiving GPS), and 10 have died (9 from disease progression). The median DFS for the entire group was 23.75 months.
Twelve patients are still alive, 9 of whom are in first complete remission and 3 after having undergone stem cell transplantation. The median OS for the entire group was 62.5 months.
Most adverse events were local irritation: 45.5% had grade 1/2 injection site reaction and 31.8% had grade 1/2 skin induration. Transient decreases in white blood cell count (27.3%) and platelet counts (18.2%) were also observed, none of which resulted in transfusion or hospitalization. Two patients discontinued therapy due to probable hypersensitivity reactions.
Immunologic correlative data were available in 14 of the 22 patients. Four of 9 had a CD4+ response, and CD4+ responses were seen across human leukocyte antigen (HLA)-Class II subtypes. Six of 7 patients had a CD8+ response, and specific CD8+ responses were observed in patients with HLA-A0201.
“There was a trend toward improved outcome with the immune responders, although this is not significant,” said Dr Maslak. Median DFS was 15 months in the 5 patients with a negative immune response and had not yet been reached in the 9 patients with an immune response. Similarly, median OS was 50.5 months and had not yet been reached in those with a negative or positive immunologic response.
“Ultimately, clinical efficacy will need to be determined in the context of a large randomized study,” he said.
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